Our Research Portfolio

The Alzheimer's Drug Discovery Foundation (ADDF) publishes all programs that we fund in our research portfolio. Funded research projects can be viewed by the year of funding or by program area, and can also be found by searching for an investigator or certain keywords. Please note that your search term(s) must contain at least four characters.

Additionally, please note that grant funding priorities at the ADDF change over time. The ADDF maintains strict confidentiality with all of our funded projects and cannot share additional information on projects without permission from the investigator(s).

The ADDF does not recommend one particular clinical trial or research program over another. The ADDF is not responsible for the accuracy of the information provided, the selection of research subjects (patients) or the conduct of the clinical trial, treatment IND/expanded access program or other research program.

Hypertension has emerged in epidemiological studies over the last 20 years as a potent risk factor not only for heart attacks and stroke, but also for Alzheimer's disease (AD) and overall brain health. Uncontrolled hypertension in midlife was independently associated with Alzheimer pathology in the brain 36 years later in the Honolulu Aging study. Cross-sectionally, in normal elders, hypertension is associated with reduced cortical thickness on brain imaging in areas vulnerable to AD. One randomized double-blind study (the Syst-Eur Study) convincingly showed that treatment of hypertension (with a calcium channel blocker) prevented decline to dementia over a four-year period. Other studies have been more equivocal. Comparative trials in hypertensive individuals between ACE inhibitors (ACEI) and angiotensin receptor blockers (sartans) have generally failed to show differences in emergent dementia, but sample sizes have often been insufficient to address this question adequately.

There exists a strong emerging rationale for a more detailed comparative study of outcomes in studies of ACEI vs. sartans. It has been recently established that angiotensin converting enzyme in the brain also catalyzes production of the toxic amyloid Beta 40-42 peptide, potentially augmenting its deposition and subsequent effects on amyloid-related pathogenesis in AD. Sartans in contrast have been shown to result in overall amyloid beta peptide catabolism through downstream effects on their receptor targets, possibly through increasing insulin degrading enzyme which directly breaks down Abeta.

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2015

Miri Polachek

Israel Brain Tech

BrainTech 2015

Conferences

$2,500

Duration: 3/11/2015-3/12/2015

Abstract:

The conference program aims to address the full life-cycle of braintech innovation - from research to commercialization - and facilitate global collaboration towards solutions that will improve millions of lives.

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2015

Ron Crystal, MD

Weill Medical College of Cornell University

Translation to the clinic of AAVrh.10-mediated Delivery to the CNS of the Apolipoprotein E2 Gene

Clinical, ApoE

$1,000,000

Duration: 1/15/2015-1/15/2016

Abstract:

Apolipoprotein E (apoE) is an important CNS apolipoprotein intimately involved in the pathogenesis of the most common late-onset familial as well as sporadic forms of Alzheimer's disease (AD). In the general population there are three common apoE alleles (apoE4, apoE3, apoE2) that encode the three common apoE isoforms expressed primarily in liver and brain. ApoE4 carriers have a markedly increased risk of developing AD (3 to 15 fold for heterozygotes to homozygotes compared to wildtype) as well as an earlier age-of-onset for developing the disease (approximately 5 years for each E4 allele compared to apoE3 homozygotes). The fact that 45-50% of Alzheimer's disease patients carry at least one apoE4 allele (compared to only 15% of age-matched healthy controls) makes apoE by far the most common genetic risk factor for the most common form of AD, a conclusion supported by multiple genetic studies, including a very large recently reported genome-wide association study. By contrast, apoE2 is a protective allele, reducing AD risk by approximately 50% and markedly delaying the age of onset, even in the presence of the apoE4 allele. Previous studies with a lentiviral vector expressing apoE2 delivered directly to the hippocampus of a transgenic AD mouse established a robust protective effect of the apoE2 allele on AD risk, with an observed rapid and robust reduction in brain amyloid burden and neuritic plaques. We extended these earlier studies on apoE2 gene delivery as a potential treatment strategy for AD by using an optimized and well-studied viral vector and explored relatively non-invasive routes of administration. Specifically, we evaluated an adeno-associated viral vector, the Rhesus serotype AAVrh.10, and multiple routes of administration (e.g. direct intracerebral / intraparenchymal, and intracisternal) in the transgenic AD mice and in healthy nonhuman primates (African green monkeys, which have a brain that better approximates that of a human) to facilitate an eventual clinical trial of apoE2 gene delivery in AD patients. These studies were designed to measure both the efficacy and preliminary safety of functional apoE2 gene delivery in a relevant disease model of AD in mice and in parallel to evaluate and optimize the capacity of the gene therapy viral vector protocol to mediate apoE2 gene expression in all of the critical disease-affected regions of the nonhuman primate brain. Our proposal leverages these data to enable a potential fast track to human clinical trial. The proposed drug will be AAVrh.10 apoE2, an rh.10 serotype AAV gene transfer vector coding for the human apoE2 coding sequence, driven by the constitutive CAG promoter. Except for the apoE2 transgene, this is the identical vector we have administered to the brain parenchyma of children with late infantile neuronal ceroid lipofuscinosis (LINCL). This project is designed to manufacture the clinical drug, and create the necessary data and documents for a pre-IND discussion with the FDA about the acceptable safety/toxicology studies required for the filing of the IND and submissions to the recombinant DNA Advisory Committee of the NIH, the Institutional Review Board, the Institutional Biosafety Committee and the Data Safety and Monitoring Board.

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2015

Matthew Disney, PhD

The Scripps Research Institute

Lead optimization and preclinical testing of small molecules that modulate toxicity of cFTD/ALS

Drug Discovery, Other Targets

$150,000

Duration: 2/1/2015-2/1/2016

Abstract:

Frontotemporal dementia (FTD) is characterized by progressive neuronal loss causing abnormalities in behavior, language and personality, characteristics that are also observed in up to 50% of amyotrophic lateral sclerosis (ALS) patients. Indeed, because of clinical, pathological and genetic overlap, FTD and ALS are considered part of a disease spectrum. No effective treatment for these devastating diseases exists, in part because of an incomplete understanding of the causative pathological mechanisms. Recently, a new therapeutic target came to light with the discovery that a G4C2 repeat expansion in C9ORF72 is the most common genetic cause of FTD and ALS. The growing body of evidence suggesting that repeat-containing RNA (r(G4C2)exp) is a key player in "c9FTD/ALS" pathogenesis provides new opportunities for the development of therapeutics that target the most common genetic abnormality causative of FTD and ALS.

Several potential mechanisms of disease have been postulated for c9FTD/ALS including loss of C9ORF72 protein function due to epigenetic changes resulting in decreased C9ORF72 mRNA expression. A strong case is mounting, however, for the involvement of RNA toxicity. For instance r(G4C2)exp transcripts, which accumulate as nuclear RNA foci, can interact with and sequester various RNA-binding proteins. r(G4C2)exp transcripts also serve as a template for the synthesis of dipeptide repeat proteins, termed c9RAN proteins, by repeat associated non-ATG (RAN) translation.

We recently reported that r(G4C2) repeats fold into two structures that are in equilibrium, a G-quadruplex and a hairpin structure that displays 1x1 GG internal loops in the stem. Using this structural information, we designed three small molecules that bind r(G4C2) repeats, one of which alleviates c9FTD/ALS defects (namely foci formation and RAN translation) in patient-derived iNeurons. Our proposed work is therefore focused on optimizing the lead compound identified from these studies by defining structure-activity relationships, modular assembly of the lead into multivalent compounds that target the repeating structure of r(G4C2)exp, and chemical similarity searching. In particular, we will study whether the compounds inhibit foci formation and c9RAN protein production, as well as penetrate the blood-brain barrier. Such studies speak to the potential of the small molecule as a pre-clinical candidate and as a tool to study c9FTD/ALS disease pathology.

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2015

Deborah Blacker, MD, ScD

Harvard Medical School

Alzheimer's Disease Modifiable Risk Database

Prevention and Risk Factor Interventions, Nutrition & Diet

$25,000

Duration: 2/1/2015-2/1/2016

Abstract:

This is a proposal to add two new risk factor entries to our AlzRisk (http://www.alzrisk.org) online compendium of epidemiologic findings on Alzheimer's disease (AD). ADDF previously supported entries on the impact on AD risk of statin use (complete, to be posted once a companion manuscript is in press) and blood lipid levels (well underway). The proposed support is for entries on vitamin D intake and on blood pressure control and specific blood pressure medications. These two risk factors offer insight into potential preventive mechanisms, and complement the existing coverage on the site. AlzRisk was launched in 2008 with the goal of providing systematic review and, where feasible, meta-analyses, on environmental risk factors for AD. The site currently has entries on 11 risk factors, with two more (statin use, as noted above, and cognitive activity) ready to post pending review of submitted manuscripts, and several more in the pipeline. It was developed in collaboration with AlzForum web developers, and aims to provide systematic review, cataloguing, and meta-analysis (where feasible) of the impact of these risk factors in the context of a rigorous methodological discussion of potential biological mechanisms, sources of bias, and threats to the validity or generalizability of the results. It is intended as a resource for the Alzheimer's disease research community and scientifically literate lay readers, similar to AlzGene, AlzForum's online compendium of Alzheimer's disease genetics findings which served as an early model for the site. While the National Institute on Aging, the Alzheimer's Association, and a variety of other sources provide general information about dementia risk factors, AlzRisk is unique in providing systematically collected, rigorously reviewed data about AD risk in a single location. Such information can be used to plan follow up research and clinical trials, to assess personal risk, to support medical recommendations and public health practice, and to generate a comprehensive risk profile to guide prevention efforts.

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2015

Sharon Rosenzweig-Lipson, PhD

AgeneBio, Inc.

Accelerating a Phase III MCI Clinical Trial with Phase I Evaluation of a Novel Extended-Release Lev

Neuroprotection, Clinical

$900,000

Duration: 2/1/2015-2/1/2016

Abstract:

Currently no FDA approved therapy exists for patients in the amnestic MCI stage of Alzheimer's disease, representing a large and growing population with an unmet clinical need. AgeneBio, Inc. has advanced a clinical program to 'slow progression in mild cognitive impairment (MCI) due to Alzheimer's disease (AD)' using the first treatment to target hippocampal hyperactivity, a condition that is characteristic of the amnestic MCI stage of the disease. The therapeutic is AGB101, a low dose extended-release formulation of the atypical antiepileptic levetiracetam. The clinical development program builds on studies in preclinical animal models and in human patients demonstrating the importance of reducing hippocampal hyperactivity for restoring brain function necessary for maintenance of cognition. Preclinical and clinical evidence further indicates that such hyperactivity contributes to neuronal injury if not controlled. The development of an extended release formulation, including Phase I studies, has been undertaken in this clinical program to optimize therapeutic benefit for patients and to minimize the time required to provide this medication to patients in the event of a successful Phase III program. Based on evidence that this treatment could slow disease progression, an indication for which the Phase III trial is designed in a two-year protocol, AGB101 could be the first therapeutic with demonstrated efficacy for modifying progression in patients at high risk for dementia. A pre-IND meeting with the FDA (March 2014) provided support on all aspects of the clinical protocol as a pivotal trial, including criteria for enrollment, adequacy of outcome measures, drug safety and CMC formulation of an extended release once-a-day medication for use in the trial. Importantly, the FDA confirmed that no further preclinical or clinical data, other than Phase I bioavailability of the new formulation would be required to proceed with the Phase III trial. AgeneBio is developing a novel low dose extended release formulation of levetiracetam suitable for once daily dosing for Phase III clinical trials and marketing. Multiple prototypes have been developed and evaluated in dog pharmacokinetic studies. Through these efforts, a 190 mg prototype (11A) has been identified that shows a delayed dissolution profile (relative to Keppra immediate release (IR) and Keppra Extended Release (XR)). In a dog PK study, 11A demonstrates bioequivalence with Keppra IR (Cmax, AUC) and Keppra XR (AUC) with a delayed release profile (comparable to Keppra XR) making it a suitable formulation for Phase I study. Continued formulation development efforts to create a 220 mg prototype have identified two additional novel formulations ready for dog PK evaluations. Following completion of the dog PK study, formulation 11A (190 mg) and the selected 220 mg formulation will be manufactured according cGMP regulations for the Phase I study. The Phase I study is a parallel 2 period crossover food effect study of the two formulations. The objective of the Phase I study is to select one of the lead formulations for the Phase III trial and to ensure that the formulation selected for Phase III trial meets the desired pharmacokinetic characteristics needed for once daily dosing and the required exposure characteristics defined by the POC MCI study (maintaining levels of 2.9 to 4.4 ug/mL).

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2015

Maria Freire, PhD

Foundation for the National Institutes of Health, Inc.

2015 Alzheimer's Disease Research Summit

Conferences

$5,000

Duration: 1/15/2015-1/15/2016

Abstract:

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2015

Thota Ganesh, PhD

Emory University

EP2 antagonists for the suppression of inflammation and neuropathology in Alzheimer's model - Year 2

Drug Discovery, Inflammation

$136,082

Duration: 1/15/2015-1/15/2016

Abstract:

Prostaglandin receptor subtype EP2 is emerging as a key promoter of inflammation and subsequent disease pathology in a variety of chronic neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease, and Amyotrophic Lateral Sclerosis. Genetic ablation of EP2 suppresses the inflammation and attenuates neurotoxicity in AD models, however, parallel data from pharmacological inhibition of EP2 in AD models is lacking. Our overarching goal is to develop an anti-inflammatory therapy for Alzheimer's disease through specific prostaglandin receptor EP2 inhibition. Thus, we like to determine whether an orally available, brain-permeant EP2 selective antagonist TG6-10-1 reduces the inflammation and neuropathology in an AD mouse model.

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2015

Charlotte Teunissen, PhD

VU University Medical Center

Novel diagnostic CSF biomarkers for pathological subtypes of FTD

Early Detection, Biochemical Biomarkers (Blood, CSF

$150,000

Duration: 2/1/2015-2/1/2016

Abstract:

Frontotemporal dementia (FTD) is the second commonest cause of early-onset dementia. Its underlying pathological spectrum, frontotemporal lobar degeneration (FTLD), can be divided in 2 main subtypes characterized by either tau or TDP-43 accumulations. Thus far, reliable biomarkers enabling the identification of FTD or distinguishing between its pathological subtypes are lacking. In the light of upcoming treatment options, such markers are highly needed.

AFTD/ADDF has previously granted a study aimed to identify cerebrospinal fluid (CSF) biomarkers for accurate diagnosis of the two main pathological subtypes of FTD using mass-spectrometry based proteomics. We included FTD patients with TDP-43 (FTD-TDP, n=12) or tau pathology (FTLD-tau, n=8), and controls with subjective memory complaints (SMC, n=10). We analysed the CSF proteome by 1D gel-nano-liquid chromatography coupled to tandem mass spectrometry. We validated several of these biomarkers in a partly overlapping larger cohort (FTLD-TDP, n=21, FTLD-tau, n=10, SMC, n=23) and also included patients with other dementias (Alzheimer's disease (AD), n=20, dementia with Lewy bodies (DLB), n=20 and vascular dementia (VaD, n=18)).

We thus identified 57 proteins that were differentially regulated (fold change>1.2, p<0.05) between the different patient groups and controls. Validation of a subset of biomarkers in a larger cohort showed that level of YKL-40 was 2-fold increased in FTD pathological subtypes compared to controls, AD, DLB, and VaD patients. The CSF levels of FABP4 were significantly increased in FTLD-tau compared to controls, AD and DLB.

These two candidates were selected for validation based on the availability of ELISA assays. However, several other biomarkers had a stronger increase, but no ELISAs were available for validation. These biomarkers are however, the most promising biomarkers for early and specific diagnosis of FTD subtypes.

The aim of the current project is therefore to validate the most promising biomarkers for use in early and specific diagnosis of FTD subtypes and define the relation of these biomarkers with the FTD pathology.

Traumatic brain injury (TBI) is associated with dementias, including Alzheimer's disease (AD) and Chronic Traumatic Encephalopathy (CTE). These post-traumatic delayed dementias are unique in their respective neuropathology and, we predict, in the evolution of neuropsychological and neuroimaging changes. We will obtain magnetic resonance imaging (MRI) and positron emission tomography (PET) data from a cohort of subjects with a TBI history and a cohort of subjects with mild cognitive impairment (and no history of TBI). The TBI cohort will include both athlete (former NCAA athletes, NFL players, and boxers) and veteran populations. MRI acquisitions will include routine clinical sequences (T1/T2/fluid attenuation inversion recovery [FLAIR]/susceptibility weighted imaging [SWI]), diffusion tensor imaging (DTI), and resting state blood oxygen level dependent (BOLD) imaging for functional connectivity. PET assessments will be performed using the ligands [18F] AV-45 (also known as Amyvid or Florbetapir) and [18F] AV-1451 (also known as T-807), a tauopathy imaging compound. In order to determine whether neurocognitive abnormalities are seen within the populations defined for the current study, we will administer a core battery of neurocognitive testing. This battery will assess cognitive abilities commonly affected by TBI, including processing speed, reaction time, new problem-solving, executive functions, attention and concentration, and learning and memory. These tests, in conjunction with the imaging, will be able to determine whether regional brain activity is associated with specific neuropsychological patterns. Additionally, we will perform integrative analyses on data acquired under the current study to compare differences in the presence of neurodegenerative disease among the represented populations and to determine biomarkers that are predictive of neurodegeneration. Accurate diagnosis is crucial in order to provide patients with appropriate treatment, and an additional biomarker tool is needed to prevent the misguided and inappropriate initiation of anti-amyloid drugs in individuals without amyloidosis who are unlikely to progress to AD.